Dana-Farber Cancer Institute
Project Term: October 1, 2020 - September 30, 2022
Dr. Kimberly Stegmaier is performing pre-clinical research to identify promising therapeutic strategies for pediatric leukemia. Pediatric blood cancers comprise about 40% of all pediatric cancers. The most common pediatric blood cancer is acute lymphoblastic leukemia (ALL), which is curable in most patients through the use of chemotherapy. Though beneficial in the short term, destroying the cancer through chemotherapy often leads to long term health problems. For those that do not respond to chemotherapy, there are fewer therapeutic options. Another pediatric blood cancer is acute myeloid leukemia (AML), which is a more aggressive and lethal disease. Therefore, many pediatric acute leukemia patients require better therapeutic options, and a precision medicine approach targeting specific mutations will likely lead to a better clinical benefit.
Many pediatric acute leukemias are associated with the fusion of parts of different chromosomes. These often cause the expression of a fusion protein made up of parts of two different proteins, and this fusion protein is often a driver of the leukemia. For pediatric acute leukemia, one of chromosomal region often rearranged contains the gene encoding the MLL protein. MLL interacts with another protein called menin and this interaction is critical for the leukemia-inducing function of MLL fusion proteins. Inhibitors blocking the interaction of MLL to menin are in clinical development, including an inhibitor funded by LLS. In addition, Dr. Stegmaier and others have identified other important mediators of the oncogenic effect of MLL fusions, and these other proteins are targeted by drugs in clinical development. Therefore, using laboratory models, Dr. Stegmaier will test the efficacy of inhibiting menin in combination with other inhibitors targeting proteins critical for the function of MLL fusions. In addition, menin inhibition is effective in AML patients with NPM1 mutations, and she will test drug combinations in models of NPM1 as well. Another fusion found in pediatric AML involves the NUP98 protein. Patients with this fusion generally do poorly. NUP98 fusions function through the interaction with another protein called CRM1. CRM1 is inhibited by selinexor, which is an FDA-approved drug used for another type of blood cancer. Dr. Stegmaier will test selinexor in laboratory models representing a number of NUP98 fusion partners. These laboratory studies may show efficacy of a particular drug or drug combination. If so, Dr. Stegmaier will consider clinical trials of these drugs in pediatric patients with fusions of MLL or NUP98, or patients with NPM1 mutations. Therefore, Dr. Stegmaier seeks to identify drugs that may be rapidly repurposed for evaluation in clinical trials for pediatric acute leukemia patients with specific molecular profiles.